This invention relates to heterocyclic compounds having pharmacological activities, their pharmaceutical compositions and their use as a medicament for treatment or prevention of diseases mediated by cGMP-PDE.
It is known that a cyclic guanosine-3xe2x80x2,5xe2x80x2-monophosphate (hereinafter referred to as cGMP) derived from a guanosine-5xe2x80x2-triphosphate possesses a relaxant activity of smooth muscle and that a cyclic guanosine-3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to catalyze the degradation of cGMP to a guanosine-5xe2x80x2-monophosphate. cGMP-PDE is a family of enzymes consists from PDE-I, II, V and so on. The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos. 579,496; 534,443; 526,004; 636,626; U.S. Pat. Nos. 3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos. 93/07,124; 94/19,351; 95/18,097; 96/32,379; Japan Patent Publication Nos. 05-222,000; 07-330,777; and so on.
Further, some kinds of benzimidazolone compounds having affinity for receptors of vasopressin and/or oxytocin are disclosed in Japanese Patent Kokai No. Hei 8(1996)-73439.
According to one aspect of this invention, it provides novel heterocyclic compounds represented by the below formula (Ia) and their pharmaceutical compositions.
According to another aspect of the invention, it provides a pharmaceutical composition for treatment or prevention of diseases mediated by cGMP-PDE (especially PDE-V) containing a heterocyclic compound represented by the below formula (I) as an active ingredient.
Specifically, the present invention provides a compound of the formula (Ia): 
wherein
Xa is CH or nitrogen atom;
Ya is oxygen atom or sulfur atom;
R1a is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group,
R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and
the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower-alkoxy-substituted aralkyl group; or two of R3a, R4a and R5a may combine together to form a lower alkylenedioxy group,
m is an integer of 1 or 2,
provided that when R3a is hydrogen atom, R4a is a lower alkoxy group and R5a is hydrogen atom, a halogen atom, cyano group, a lower alkyl group, a lower alkoxy group, a protected carboxy group, carboxy group or nitro group then
1) the lower alkyl group for R2a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl,
2) the cycloalkyl group for R2a has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
3) the heterocyclic group for R2a is selected from pyrrolidinyl group, dioxanyl group and piperidyl group which groups may be substituted with protected carboxy, acyl, lower alkanesulfonyl, carbamoyl or sulfamoyl,
(4) R1a is carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; an acyl group; or a lower alkanesulfonyl group;
(5) Xa is nitrogen atom;
(6) m is an integer of 2; or
(7) Ya is sulfur atom,
its prodrug or a pharmaceutically acceptable salt thereof.
According to the present invention, it also provides a pharmaceutical composition directed to treatment or prevention of diseases mediated by cGMP-PDE which comprises a compound of the formula (I): 
wherein
X is CH or nitrogen atom;
Y is oxygen atom or sulfur atom;
R1 is a halogen atom, cyano group, nitro group, carbamoyl group, a lower alkylcarbamoyl group which may be substituted with a heterocyclic group, carboxy group, a protected carboxy group, a lower alkyl group, a halo(lower)alkyl group, a lower alkoxy group, an acyl group or a lower alkanesulfonyl group,
R2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and
the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
R3, R4 and R5 are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower-alkoxy-substituted aralkyl group, or two of R3, R4 and R5 may combine together to form a lower alkylenedioxy group,
n is an integer of 1 or 2,
its prodrug or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or diluent.
The present invention further provides an intermediate compound of the following formula (II) or its salt for preparing a compound (I). 
wherein
X is CH or nitrogen atom;
Y is oxygen atom or sulfur atom;
R1 is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, and
R2 is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and
the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl.
In the above and subsequent descriptions of the present specification, preferable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.
In this respect, it is to be noted that the following explanations are given by referring to R1 to R5, X and Y and that R1a to R5a, Xa and Ya are the same as R1 to R5, X and Y or included therein, respectively.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atoms, unless otherwise indicated.
Preferably, the halogen atoms for R1, R3, R4 and R5 are fluorine, chlorine, bromine and iodine.
Preferably, the lower alkyl groups for R1, R2, R3, R4 and R5 are straight or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and the like.
Preferably, the halo(lower)alkyl group for R1 is lower alkyl groups substituted with one or more halogen atoms, in which the lower alkyl moiety and the halogen atom may be the same as exemplified in the above, respectively. Preferred examples of the halo(lower)alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, iodomethyl, fluoroethyl, 2,2,2-trifluoroethyl, chloroethyl, 2,2,2-trichloroethyl, bromoethyl, iodoethyl, chloropropyl, bromopropyl, chlorobutyl, bromobutyl, chloropentyl, bromopentyl, chlorohexyl, bromohexyl and the like.
Preferably, the lower alkoxy groups for R1, R3 R4 and R5 are straight or branched chain ones having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
Preferably, the acyl group for R1 is lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl), aroyl (e.g., benzoyl, toluoyl, xyloyl and naphthoyl), heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl and furoyl) and the like.
Preferably, the lower alkanoyl groups for R3, R4 and R5 are the same as those illustrated as lower alkanoyl included in the acyl group for R1.
Preferably, the lower alkanesulfonyl group for R1 is straight or branched one having 1 to 6 carbon atoms such as methanesulfonyl(mesyl), ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, 2-methylpropanesulfonyl and the like.
Preferably, the protected carboxy group for R1, R3,R4 and R5 is carboxy groups protected by a conventional protecting group. Examples of the protected carboxy group include lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and isopropoxycarbonyl), ar(lower)alkyloxycarbonyl (e.g., benzyloxycarbonyl, trityloxycarobonyl, 4-methoxybenzyloxycarobnyl, 4-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, bis(methoxyphenyl)methyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl and benzhydryloxycarbonyl) and the like.
The lower alkyl moiety of the lower alkylcarbamoyl group for R1 is the same as the lower alkyl group as illustrated in the above, and said lower alkyl moiety may be substituted with a heterocyclic group as illustrated below. Examples of the lower alkylcarbamoyl group are methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and the like. Examples of the lower alkylcarbamoyl group substituted with a heterocyclic group are furfurylcarbamoyl, thenylcarbamoyl, pyridylmethylcarbamoyl, pyrrolylmethylcarbamoyl, and the like.
Preferably, the cycloalkyl group for R2 is cyclic saturated hydrocarbon residues having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Preferably, the heterocyclic group for R2 is saturated or unsaturated, monocyclic or condensed one containing one or more hetero atoms selected from nitrogen, sulfur and oxygen atoms, such as
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pirazolidinyl, piperidino, piperidyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl], tetrazolyl [e.g., 1H-tetrazoly or 2H-tetrazolyl] or the like;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms, for example, pyranyl, furyl, dioxanyl, tetrahydropyranyl, tetrahydrofuryl or tetrahydrodioxanyl;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, thiopyranyl or the like;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or the like;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholino or morpholinyl;
saturated or unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl, thiomorpholino or thiomorpholinyl;
unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atoms, for example, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, quinolyl, isoquinolyl, indolyl or the like;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms, for example, benzofuryl or the like;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl or the like;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzisothiazolyl, phenothiazinyl or the like.
Preferably, the aralkyl groups for R3, R4 and R5 are lower alkyl group substituted with one or more aryl groups. Examples of the aralkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl, naphthylmethyl, tolylmethyl, xylylmethyl, mesitylmethyl and the like.
Further, preferable examples of each substituents on the lower alkyl group, cycloalkyl group and heterocyclic group for R2 and the aralkyl group for R2, R3 and R4 are explained in the following.
Examples of the acyloxy group are lower alkanoyloxy (e.g., formyloxy, acetyloxy, propionyloxy and butyryloxy), aroyloxy (e.g., benzoyloxy, toluoyloxy and naphthoyloxy), heterocyclic carbonyloxy (e.g., nicotinoyloxy, isonicotinoyloxy and furoyloxy) and the like.
Examples of the acyloxy(lower)alkyl group are lower alkanoyloxy(lower)alkyl (e.g., formyloxymethyl, acetoxymethyl, propionyloxymethyl and butyryloxymethyl), aroyloxy(lower)alkyl (e.g., benzoyloxymethyl, toluoyloxymethyl and naphthoyloxymethyl), heterocyclic carbonyloxy(lower)alkyl (e.g., nicotinoyloxymethyl, isonicotinoyloxymethyl and furoyloxymethyl), and the like.
The acyl group and acyl moiety in the acyloxy, acylamino and acyloxy(lower)alkyl groups are the same as those illustrated as the acyl group for R1.
Examples of the acylamino group are lower alkanoylamino (e.g., formylamino, acetylamino, propionylamino and butyrylamino), aroylamino (e.g., benzoylamino, toluoylamino and naphthoylamino), heterocyclic carbonylamino (e.g., nicotinoylamino, isonicotinoylamino and furoylamino) and the like.
Suitable protective group in the protected hydroxy and protected hydroxy(lower)alkyl groups may include acyl, mono (or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), tri-substituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
The protected carboxy group is the same as those illustrated as the protected carboxy group for R1.
The lower alkoxycarbonylamino group is methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino and the like.
The lower alkanesulfonyl group and the lower alkanesulfonyl moiety in the lower alkanesulfonylamino group are the same as those illustrated as the lower alkanesulfonyl group for R1. Examples of the lower alkanesulfonylamino group are methanesulfonylamino, ethanesulfonylamino and propanesulfonylamino.
The lower alkylureido group is methylureido, ethylureido, propylureido, isopropylureido, butylureido, isobutylureido, tert-butylureido, pentylureido, hexylureido and the like.
The lower alkyl group and lower alkyl moieties in the hydroxy(lower)alkyl, acyloxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkyl ureido, lower alkyl amino, lower alkyl carbamoyl groups are the same as those illustrated as the lower alkyl group for R1 to R5. Examples of hydroxy(lower)alkyl group are hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl. Examples of protected hydroxy(lower)alkyl are acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, benzyloxymethyl, benzyloxyethyl, 4-methoxybenzyloxymethyl, 4-methoxybenzyloxyethyl, trityloxymethyl, trityloxyethyl, trimethylsilyloxymethyl, trimethylsilyloxyethyl, tert-butyldimethylsilyloxymethyl, tert-butyldimethylsilyloxymethyl, tetrahydropyranyloxymethyl and tetrahydropyranyloxyethyl. Examples of lower alkyl ureido group are methylureido, ethylureido, propylureido and butylureido. Examples of lower alkyl amino group are mono- or di-lower alkylamino group such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, butylamino. Examples of lower alkyl carbamoyl group are methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl and butylcarbamoyl.
The lower alkyl group is substituted with one or more protected hydroxy groups having the acyl moiety as illustrated before.
The lower alkylenedioxy group is methylenedioxy, ethylenedioxy, propylenedioxy, isopropylidenedioxy and the like.
The aralkyloxy group is benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, benzhydryloxy, trityloxy, naphthylmethoxy, tolylmethoxy and the like.
The lower alkoxy group in the lower-alkoxy-substituted aralkyloxy group is the same as those illustrated as the lower alkoxy group for R1, R3, R4 and R5. Examples of the lower-alkoxy-substituted aralkyloxy group include 3,4-dimethoxybenzyloxy, 3,4-dimethoxyphenethyloxy, 3,4-dimethoxyphenylpropoxy, 3,4-dimethoxyphenylbutoxy, 3,4-dimethoxyphenylpentyloxy, 3,4-dimethoxyphenylhexyloxy, 4,4xe2x80x2-dimethoxybenzhydryloxy, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityloxy and the like.
The lower alkoxy groups in the lower-alkoxy-substituted aralkyl group for R3, R4 and R5 are the same as those illustrated as the lower alkoxy group for R1, R3 to R5. Examples of the lower-alkoxy-substituted aralkyl group include 3,4-dimethoxybenzyl, 3,4-dimethoxyphenethyl, 3,4-dimethoxyphenylpropyl, 3,4-dimethoxyphenylbutyl, 3,4-dimethoxyphenylpentyl, 3,4-dimethoxyphenylhexyl, 4,4xe2x80x2-dimethoxybenzhydryl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl and the like.
Furthermore, the lower alkylenedioxy group formed by the combination of two adjacent alkoxy groups for R3 to R5 is methylenedioxy, ethylenedioxy, propylenedioxy, isopropylidenedioxy and the like.
When the lower alkyl group, cycloalkyl group or heterocyclic group for R2 is substituted with two or three substitutes, those substitutes may be the same or different each other.
Further, in the lower-alkoxy-substituted aralkyloxy group for R2 or the lower-alkoxy-substituted aralkyl group for R3 to R5, the aralkyloxy or aralkyl group may be substituted with the two lower alkoxy which are the same or different each other.
It is to be noted that a hydrogen atom of CH for X can be also replaced with the substituent R1 to form CR1.
The pharmaceutically acceptable salts may be, for example, a salt with an alkali metal (e.g., sodium or potassium) and an alkaline earth metal (e.g., calcium or magnesium), an ammonium, an organic base (e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or dibenzylethylenediamine), an organic acid (e.g., acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, formic acid, p-toluenesulfonic acid or trifluoroacetic acid), inorganic acid (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid), an amino acid (e.g., arginine, aspartic acid or glutamic acid) or the like.
The compounds of the formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers.
The compounds of the formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may also exist in tautomeric forms and this invention includes both mixtures and separate individual tautomers.
It is further to be noted that isomerization or rearrangement of the compounds (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
The compounds of the formula (I) and (la), their prodrugs and pharmaceutically acceptable salts thereof can be in the form of solvates, which are included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of the invention are radiolabelled derivatives of compounds of formula (I) and (Ia), their prodrugs and pharmaceutically acceptable salts thereof which are suitable for biological studies.
Preferred embodiments of the compound are represented by the formula (Ia), wherein Xa is nitrogen atom and R1a-R5a, Ya and m are the same as those defined before,
its prodrug or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the compounds are represented by the formula (Ia), wherein
R1a is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a lower alkoxycarbonyl group; a lower alkyl group; a halo(lower)alkyl group; a lower alkanoyl group; an aroyl group; or a lower alkanesulfonyl group,
R2a is a cycloalkyl group which has one to three substituents selected from the group consisting of hydroxy, acyloxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, lower alkoxycarbonyl, lower alkanesoulfonyl, lower alkyl, hydroxy(lower)alkyl, acyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl, and sulfamoyl; and
Xa, Ya, R3a, R4a, R5a and m are the same as those defined before,
its prodrug or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the compounds are represented by the formula (Ia), wherein
R1a is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a lower alkoxycarbonyl group; a lower alkyl group; a halo(lower)alkyl group; a lower alkanoly group; an aroyl group; or a lower alkanesulfonyl group,
R2a is a cyclohexyl group which has one to three substituents selected from the group consisting of hydroxy, lower alkanoyloxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, lower alkoxycarbonyl, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, lower alkanoyloxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl; and
Xa, Ya, R3a, R4a, R5a and m are the same as those defined before,
its prodrug or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the compounds are represented by the formula (Ia), wherein
R1a is cyano group,
R2a is a cyclohexyl group which has hydroxy or lower alkanoyloxy,
R3a is a hydrogen atom,
R4a is a halogen atom,
R5a is a lower alkoxy group,
Xa, Ya and m are the same as those defined before,
its prodrug or a pharmaceutically acceptable salt thereof.
Another preferred embodiments of the compound are represented by the formula (Ia), wherein
Xa is CH;
Ya is oxygen atom or sulfur atom;
R1a is cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; an acyl group; or a lower alkanesulfonyl group,
R2a is a lower alkyl group, a cycloalkyl group or a heterocyclic group, each of which has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl;
R3a, R4a and R5a are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower-alkoxy-substituted aralkyl group; or two of R3a, R4a and R5a may combine together to form a lower alkylenedioxy group,
m is an integer of 1,
its prodrug or a pharmaceutically acceptable salt thereof.
The most preferred embodiments of the compounds are
1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one,
1-(3-bromo-4-methoxybenzyl)-6-cyano-3-(trans4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one, and
1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(cis-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one.
According to the present invention, the above mentioned compound (I), its prodrug or pharmaceutically acceptable salt thereof is used as a pharmaceutical composition or medicament usually in admixture with a pharmaceutically acceptable carrier or diluent.
Preferred embodiments of the pharmaceutical composition of the present invention contain a compound of the formula (I), wherein X is nitrogen atom and R1-R5, Y and n are the same as those defined before, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with a pharmaceutically acceptable carrier or diluent.
Another preferred embodiments of the pharmaceutical composition contain a compound of the formula (I), wherein R2 is a cycloalkyl group which may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl, and X, Y, R1, R3, R4, R5 and n are the same as those defined in the above, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with a pharmaceutically acceptable carrier or diluent.
The prodrug of the compound (Ia) is intended to mean a chemically modified derivative of the compound (Ia) which itself does not show a pharmacological activity but may be catalytically or non-catalytically decomposed or metabolized in human or animal bodies into its pharmacologically active form. Examples of the prodrugs of the compounds (Ia) are easily hydrolyzeable esters of the compounds (Ia).
According to this invention, the compound (I) or its salts can be prepared by the following process. 
In the above formula, R1, R2, R3, R4, R5, X, Y and n are the same as above and Z1 is a halogen atom.
Some of the starting materials are novel and can be prepared by the following process. 
In the above formula, R1, R2, X and Y are the same as above, and Z is a halogen atom or hydroxy group.
The processes for preparing the starting compounds and the final compounds (I) and (Ia) of the present invention are explained in detail in the following.
Process 1
A compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (III).
This reaction is usually carried out in the presence of an inorganic or organic base.
Preferable inorganic bases include an alkali metal [e.g., sodium or potassium], an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide], an alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate or potassium hydrogen carbonate], an alkali metal carbonate [e.g., sodium carbonate], an alkaline earth metal carbonate [e.g., calcium carbonate], an alkali metal hydride [e.g., sodium hydride or potassium hydride] and the like.
Preferable organic bases include tri(lower)alkylamines [e.g., triethylamine or N,N-diisopropylethylamine], alkyl lithiums [e.g., methyl lithium or butyl lithium], lithium diisopropylamide, lithium hexamethyldisilazido and the like.
The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
In the case where the compound (I) contains a group for R1 and/or R2 which can be converted to another group belonging to R1 and/or R2 respectively, said compound (I) can be optionally converted to another compound (I) by a conventional method.
For example, a compound (I) containing a protected carboxy group can be hydrolyzed with an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide] to give a compound (I) containing carboxy group. Further, a compound (I) containing amino group can be reacted with metal isocyanate (e.g., potassium isocyanate) to give a compound (I) containing ureido group.
Concretely, such conversions can be carried out in accordance with a method described in Examples or by a similar method thereto.
A pharmaceutically acceptable salt of the compound (I) and (Ia) and their prodrugs can be prepared by treating a compound (I) and (Ia) and their prodrugs with an appropriate base or acid in accordance with the conventional method, respectively.
Process A
A compound (II) or its salt can be prepared by
1) aminating a compound (IV) or its salt with a compound (V) to give a compound (VI) or its salt,
2) reducing a nitro group of the compound (VI) or its salt to give a compound (VII) or its salt, and then
3) intramolecular-cyclizing two amino groups of the compound (VII) or its salt by using a coupling agent as illustrated in Preparations or by a similar method thereto.
Process A-1)
A compound (IV) or its salt can be aminated with an amine compound (V) to give a compound (VI) or its salt. Amination condition can vary depend on the group Z of the compound (IV) or its salt. When Z is a halogen atom such as fluorine or chlorine, amination can occur between the compound (IV) or its salt and the amine compound (V) under mild heating without any particular activation of the group Z of the compound (IV) or its salt. When the group Z is hydroxy, the hydroxy group for Z needs to be activated by the reaction with SOCl2 or mesyl chloride. Then, activated compound (IV) or its salt can be aminated with the amine compound (V) at room temperature or under cooling. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
Process A-2)
A compound (VI) or its salt can be reduced by a well-known method in the art such as catalytic reduction. The reduction is carried out in a conventional manner, including a chemical reduction and a catalytic reduction.
Suitable reducing agents to be used in the chemical reduction are a combination of metals (e.g., tin, zinc or iron) or metallic compounds (e.g., chromium chloride or chromium acetate) and organic or inorganic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid or hydrobromic acid).
Suitable catalysts to be used in the catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide or platinum wire), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate or palladium on barium carbonate), nickel catalysts (e.g., reduced nickel, nickel oxide or Raney nickel), cobalt catalysts (e.g., reduced cobalt or Raney cobalt), iron catalysts (e.g., reduced iron or Raney iron), copper catalysts (e.g., reduced copper, Raney copper or Ullman copper) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran or a mixture thereof. Additionally, in the case where the above-mentioned acid to be used in the chemical reduction is in liquid, it can also be used as a solvent.
The reaction is usually carried out under cooling to warming since the reaction temperature of the reduction is not critical.
In the case where the compound (VI) or its salt contains a group for R1 and/or R2 which can be converted to another group belonging to R1 and/or R2 respectively, said compound (VI) or its salt can be optionally converted to another compound (VI) or its salt by a conventional method. For example, a compound (VI) or its salt containing a hydroxy group can be acylated with acyl chloride [e.g., acetyl chloride] to give a compound (VI) or its salt containing an acetoxy group. Further, a compound (VI) or its salt containing an amino group can be reacted with di-tert-butyl dicarbonate to give a compound (VI) or its salt containing a tert-butoxycarbonyl group.
Process A-3)
A compound (VII) or its salt can be intramolecular-cyclized by a coupling agent such as 1,1xe2x80x2-carbonyldiimidazole, triphosgene or 1,1xe2x80x2-thiocarbonyldiimidazole. The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof. The reaction is usually carried out under cooling to heating since the reaction temperature is not critical.
The compounds (I) including the compounds (Ia) and pharmaceutically acceptable salts thereof possess inhibitory activity of cGMP-PDE (especially PDE-V) known to be involved in relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, relaxant activity of the penile corpus cavernosum, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on.
Therefore, the compounds (I) including the compounds (Ia) and pharmaceutically acceptable salts thereof may be useful for the treatment or prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases (e.g., diabetic glomerulosclerosis), renal tubulo-intestitinal diseases (e.g., nephropathy induced by tacrolimus, cyclosporin or the like), renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g., post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, stroke, chronic reversible obstructive lung diseases (e.g., bronchitis or asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility (e.g., irritable bowel syndrome), erectile dysfunction (e.g., organic erectile dysfunction or psychic erectile dysfunction), female sexual dysfunction, impotence, or diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermopathy, diabetic neuropathy, diabetic cataract or diabetic retinopathy).
Specifically, the compounds (I) and (Ia) and pharmaceutically acceptable salts thereof are also useful for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder (such as the ones ascribed to nerve regressive affection, inflammation, injury, neoplasm, diabetes mellitus, cerebral vascular accident, surgery, prostatomegaly, urethra relaxation incompetence, dysuria).
It is to be noted that improvement of sexual performance is also included in the treatment of erectile dysfunction or impotence.
The compounds (I) and (Ia) and their salts of the present invention have much advantages, such as stronger activity, more suitable half-life, decreased adverse effect, or the lie, compared to the known anthranilic acid derivatives having an inhibitory activity of cGMP-PDE, which are shown in the prior arts.
In order to exhibit the usefulness of the present invention, the activities of the compounds (I) are shown in the following.
[I] Test Compound
The test compounds were obtained in each Example shown in Table 1.
[II] Test Method: cGMP-Phosphodiesterase (PDE) Assay
Human platelet cGMP-PDE was separated from other isozymes in human platelets by a modification of the method of Thompson et. al. (see Cyclic Nucleotide Phosphodiesterase (PDE), in Methods of Enzymatic analysis, Vol 4, p127-234, 1984). Specific inhibitory activity of PDE-V was measured by following procedure. In enzyme inhibition assays, the test compounds were dissolved in DMSO and then diluted with assay buffer (50 mM Tris-HCl, 0.077 mg/ml dithiothreitol and 10 mg/ml snake venom, 1 mM EGTA, pH 8.0), at final concentrations ranging from 10xe2x88x9210 to 10xe2x88x926 M. Assays were performed at 0.1 xcexcM substrate ([3H]-cGMP) concentration, at 30xc2x0 C. for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis of substrate. Each assay was initiated by addition of substrate and terminated by addition of anion exchange resin (Dowex(copyright) 1-X8, 250 mg/mg) followed by centrifugation for 10 minutes (3000 rpm, at 4xc2x0 C.). Radioactivity of supernatant ([3H]-GMP) was assayed by liquid scintillation counting.
The results in enzymatic inhibitory test against human platelet PDE-V are shown in Table 1.
As shown in the above Table 1, the compounds (I) of the present invention have superior inhibitory activity against cGMP-PDE.
The compound (Ia), its prodrug and its salt can be administered alone and the compound (Ia) and (I), their prodrugs and their salts can be administered in a form of a composition in admixture of a pharmaceutical acceptable carrier or diluent.
The active ingredient of this invention can be used in a form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (Ia) or (I), its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient, in admire with an organic or inorganic carrier or diluent suitable for external, enteral, intravenous, intramuscular, parenteral or intramucous applications. The active ingredient may be compounded, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use.
The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
The active ingredient may be compounded into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes (oral mucous membrane, fascia penis, facies urethralis penis, etc.).
Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.
While the dosage of therapeutically effective amount of a compound (I) or (Ia), its salt or a pharmaceutically acceptable salt thereof varies from and also depends upon the age and condition of each individual patient to be treated, in case of the systemic administration, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.3 mg/body to 1,000 mg/body.
The patents, patent applications and publications cited herein above are incorporated by reference.